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IE900996L - Use of adamantane derivatives for the prevention and¹treatment of cerebral ischaemia - Google Patents

Use of adamantane derivatives for the prevention and¹treatment of cerebral ischaemia

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Publication number
IE900996L
IE900996L IE900996A IE99690A IE900996L IE 900996 L IE900996 L IE 900996L IE 900996 A IE900996 A IE 900996A IE 99690 A IE99690 A IE 99690A IE 900996 L IE900996 L IE 900996L
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Prior art keywords
adamantane
amino
ethyl
hydrogen
use according
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IE900996A
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IE63467B1 (en
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Joachim Bormann
Markus R Gold
Wolfgang Schatton
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Merz & Co Gmbh & Co
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/34—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton
    • C07C211/38—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton containing condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
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  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Neurology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Epidemiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Cardiology (AREA)
  • Psychiatry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicinal Preparation (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

The use of adamantane derivatives of the general formula <IMAGE> in which R1 and R2 are identical or different and are hydrogen or straight-chain or branched alkyl groups with 1 to 6 C atoms, or together with N are a cycloalkyl group with 5 or 6 ring members, R3 and R4 are each identical or different and are selected from hydrogen, a straight-chain or branched alkyl radical with 1 to 6 C atoms, a cycloalkyl radical with 5 or 6 C atoms, the phenyl radical, and in which R5 is hydrogen or a straight-chain or branched C1-C6-alkyl radical, and the pharmaceutically tolerated salts thereof for the production of a medicament for the prevention and treatment of cerebral ischaemia.

Description

63467 The present invention relates to the use of adamantane derivatives corresponding to the general formula R%>/R2 wherein R^ and R2 are identical or different and denote hydrogen or straight chain or branched alkyl groups having 5 1 to 6 carbon atoms or together with N they form a heterocyclic group having 5 or 6 ring members, R3 and R4 are identical or different and are selected from hydrogen, a straight chain or branched alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 5 or 6 carbon 10 atoms and the phenyl group, and R5 denotes hydrogen or a straight chain or branched Cj-Cg-alkyl group. The straight chain or branched C1-C6-alkyl groups may be methyl, ethyl, iso- or n-propyl, n- or isobutyl, n-pentyl or n-hexyl or isomers thereof. 1 The compounds are suitable for treating the damage to neurones resulting from an excessive calcium excess over NMDA receptor channels, in particular after cerebral ischaemia.
The invention also covers the pharmaceutically acceptable acid addition salts of the above-mentioned compounds.
Certain 1-amino-adamantanes of formula (I) are known per se. Thus, for example, l-amino-3,5-dimethyladamantane is the subject matter of DE-PS 22 19 256 and DE-PS 28 56 393.
Some 3,5-disubstituted 1-amino-adamantanes of formula (I) are described in US-PS 4 122 193. l-Amino-3-ethyl-adamantane is described in DE-PS 22 32 735.
Compounds of formula (I) are generally prepared by the alkylation of halogen-adamantane, preferably bromo-15 or chloro-adamantane. Subsequent further halogenation and alkylation results in the individual di- and tri-substituted adamantanes.
Introduction of the amino function takes place either by oxidation with chromium trioxide and bromination with HBR 20 or bromination with bromine and reaction with formamide followed by hydrolysis. Alkylation of the amino function may be carried out by well-known methods. Thus, for example, methylation may be carried out by a reaction with chloroformic acid methyl ester followed by reduction. 25 The ethyl group may be introduced by reduction of the corresponding acetamide.
Amination may also be carried out according to US-A-4 122 193 by reaction of the corresponding l-halogen-3,5-or 7-substituted compounds with a urea derivative 2 corresponding to the following formula H O H \ II / N - C - N / \ Rl Rj. followed, if desired, by further alkylation of the amino function.
The preparation of the compounds according to formula (I) 10 is represented in the reaction scheme shown below: Reaction scheme Ad = adamantyl radical Hal = CI, Br Ad-Hal Alkylation (R3) Ad-R3 Alkylation (R4) Alkylation (R5) R5 HCONH2 h+/h2o NHo I Ad-R3 Ad-R3 I l4 1 HC0NH2 h+/h2o 1 NH-> I Ad-R-i I . ?4 1 Ad-R3 HC0NH2 h+/h2o i NH-, I Rc-Ad-Rr Selective Introduction of /R2 3 Alkylation of the halogen-adamantanes may be carried out, for example, by a Friedel-Crafts-Reaction (introduction of the phenyl group) or by reaction with vinylidene chloride followed by reduction and a suitable Wittig reaction of 5 the aldehydes and their hydrogenation or by the insertion of ethylene followed by alkylation with the corresponding cuprates or by the insertion of ethylene and reduction of the halogen-alkyl-adamantanes or by acylation with C02 and reduction of the carboxylic acids in known manner.
The compounds of formula (I) known from the above-mentioned publications have hitherto been used as agents for the treatment of Parkinson's disease and Parkinsonlike diseases. Their action is attributed to a dopaminergic influence of the CNS brought about either by increased 15 release or by inhibition of uptake of the transmitter substance, dopamine. The imbalance in the dopamine/acetyl choline system is thereby eliminated.
The effect of dopaminergic stimulants, inter alia 1-amino-adamantane, on the coma-EEG is investigated in 20 J.Pharmacol., 13., 163-164, 1982. It is also shown that haloperidol cancels the re-establishment of disturbed EEG activity achieved by adamantane since haloperidol is a dopamine antagonist.
Dopaminergic substances leading acutely to an EEG 25 activation in pons-ischaemic rats are investigated in Japan J. Pharmacol. 39, 443-451, 1985.
The effect of 1-amino-adamantane in coma patients is investigated in Arzneimittelforschung 32., 1268-1273, 1982, and the effect of this substance on the catecholamine 30 metabolism is described. 4 The acute disappearance of characteristic EEG changes after L-dopa- and adamantine therapy in patients with Jakob-Creutzfeldt Disease is explained in the publication "British Medical Journal, 3, 272-273, 1973, the effect of 5 the compounds being attributed to their dopaminergic influence.
US-A 3 450 761 discloses amino-adamantanes, inter alia l-amino-3-ethyl-5,7-dimethyl-adamantane, which have an anti-viral action.
In contrast to this type of diseases, cerebral ischaemia is a pathophysiological situation in which the neuronal excitator mechanisms get out of balance. The excessive influx of calcium along N-methyl-D-aspartate(NMDA) receptor channels finally results in the destruction of 15 nerve cells of certain areas of the brain (Rothmann & Olney, Trends Neurosci H), 1987, 299 et seq).
It would therefore appear that an intervention which is antagonistic with respect to the NMDA receptor channels is necessary for the treatment or elimination of this patho-20 logical situation (Kemp et al, Trends Pharmacol., Sci. 8, 1987, 414 et seq) .
Such intervention may take place, for example, with substituted fluoro- and hydroxy derivatives of dibenzo-[a,d]-cyclohepten-5,10-imine, which are described in EP-A 25 0 264 183.
These heterocyclic aromatic compounds are lipophilic and have NMDA receptor channel-antagonistic and anticonvulsive properties. They are produced by a relatively complicated process in which enantiomeric mixtures are formed which 30 can be separated into the individual optical antipodes.
It is an object of the present invention to provide chemically readily available compounds having an NMDA receptor channel-antagonistic action and an anticonvulsive action for the prevention and treatment of cerebral 5 ischaemia.
The invention solves this problem by the use of 1-amino-adamantanes of formula (I).
It was surprisingly found that the damage to brain cells after ischaemia can be prevented by using these compounds. 10 The adamantane derivatives corresponding to formula (I) are therefore suitable for the prevention and therapy of cerebral ischaemia after a stroke, cardiac operations, cardiac arrest, subarachnoidal bleeding, transient cerebral ischaemic attacks, perinatal asphyxia, anoxia, 15 hypoglycaemia, apnoea and Alzheimer's disease.
The following are examples of compounds according to the invention: 1-Amino-adamantane l-amino-3-phenyl-adamantane ^ * 1-amino-methyl-adamantane l-amino-3,5-dimethyl-adamantane (Test compound No. 1) l-amino-3-ethyl-adamantane (Test compound No. 2) l-amino-3-isopropyl-adamantane (Test compound No. 3) l-amino-3-n-butyl-adamantane 25 l-amino-3,5-diethyl-adamantane (Test compound No. 4) l-amino-3,5-diisopropyl-adamantane l-amino-3,5-di-n-butyl-adamantane l-amino-3-methyl-5-ethyl-adamantane l-N-methylamino-3,5-dimethyl-adamantane 30 (Test compound No. 5) 6 l-N-ethyl-l-amino-3,5-dimethyl-adamantane (Test compound No. 6) l-N-isopropyl-amino-3,5-dimethyl-adamantane l-N,N-dimethyl-amino-3,5-dimethyl-adamantane 5 l-N-methy 1-N-isopropy l-amino-3 -methyl-5-ethy 1-adamantane l-amino-3-butyl-5-phenyl-adamantane l-amino-3-penty1-adamantane l-amino-3,5-dipentyl-adamantane l-amino-3-pentyl-5-hexy1-adamantane 10 l-amino-3-pentyl-5-cyclohexy1-adamantane l-amino-3-pentyl-5-pheny1-adamantane l-amino-3-hexy1-adamantane l-amino-3,5-dihexyl-adamantane l-amino-3-hexyl-5-cyclohexy1-adamantane 15 l-amino-3-hexyl-5-phenyl-adamantane l-amino-3-cyclohexyl-adamantane (Test compound No. 7) l-amino-3,5-dicyclohexyl-adamantane l-amino-3-cyclohexyl-5-pheny1-adamantane l-amino-3,5-diphenyl-adamantane 2 0 l-amino-3,5,7-trimethyl-adamantane l-amino-3,5-dimethyl-7-ethyl-adamantane (Test comp. No.8) l-amino-3, 5-diethyl-7-methyl-adamantane and their N-methyl-, N,N-dimethyl-, N-ethyl-, N-propyl-, 1-N-pyrrolidino- and 1-N-piperidino-derivatives 25 l-amino-3-methyl-5-propy1-adamantane l-amino-3-methy1-5-buty1-adamantane l-amino-3-methyl-5-penty1-adamantane l-amino-3-methyl-5-hexy1-adamantane l-amino-3-methyl-5-cyclohexy1-adamantane 30 l-amino-3-methyl-5-pheny1-adamantane l-amino-3-ethyl-5-propyl-adamantane l-amino-3-ethy1-5-buty1-adamantane l-amino-3-ethyl-5-penty1-adamantane l-amino-3-ethyl-5-hexy1-adamantane 35 1-amino-3-ethy1-5-cyclohexy1-adamantane 7 l-amino-3-ethy1-5-pheny1-adamantane l-amino-3-propy1-5-buty1-adamantane l-amino-3-propyl-5-pentyl-adamantane l-amino-3-propyl-5-hexyl-adamantane 5 l-amino-3-propy1-5-cyclohexy1-adamantane l-amino-3-propyl-5-phenyl-adamantane l-amino-3-butyl-5-penty1-adamantane l-amino-3-butyl-5-hexyl-adamantane l-amino-3-butyl-5-cyclohexyl-adamantane 10 and the acid addition compounds thereof.
Preferred compounds of formula (I) are those in which R^ and R2 stand for hydrogen, e.g. l-amino-3-ethyl-5,7-dimethyl-adamantane, and compounds in which R^, R2, R4 and R5 stand for hydrogen, e.g. l-amino-3-cyclohexyl-adaman-15 tane and l-amino-3-ethyl-adamantane.
Other preferred compounds are those in which R^, R2 and R5 stand for hydrogen, e.g. l-amino-3-methyl-5-propyl- or -5-butyl-adamantane, l-amino-3-methyl-5-hexyl- or -cyclo-hexyl-adamantane or l-amino-3-methyl-5-phenyl-adamantane. l-Amino-3,5-dimethyl-adamantane and l-amino-3, 5-diethyl-adamantane are particularly preferred compounds, i.e. compounds in which R^, R2 and R5 denote hydrogen as well as those in which R^ and R5 denote hydrogen, R2 denotes methyl or ethyl and R3 and R4 both denote methyl, e.g. 1-25 N-methyl-amino-3, 5-dimethyl-adamantane and 1-N-ethylamino-3,5-dimethyl-adamantane.
The adamantane derivatives of formula (I) may be administered as such or in the form of their pharmaceutically acceptable acid addition salts such as, for example, the 30 hydrochlorides, hydrobromides, sulphates, acetates, 8 succinates or tartrates or compounds of addition with fumaric, maleic, citric or phosphoric acid.
The compounds of formula (I) are administered in a suitable form in quantities of about 0.01 to 100 mg/kg. 5 Suitable forms of administration are, for example, combinations of the active substance with conventional pharmaceutical carriers and auxiliary agents in the form of tablets, coated tablets, sterile solutions or injections. Suitable pharmaceutical^ acceptable carriers are, 10 for example, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, gum arabic, corn starch or cellulose used together with diluents such as water, polyethylene glycol, etc. Solid forms of administration are prepared by the usual methods and may contain up to 50 15 mg of active substance per unit.
The activity of the compounds of formula (I) is illustrated below with the aid of pharmacological investigations .
A. Displacement of the TCP bond % •N Phencyclidine (PCP), a well known NMDA antagonist, attaches to the ionic channel associated with the NMDA receptor and blocks the transport of ions (Garthwaite & Garthwaite, Neurosci. Lett.83, 1987, 241-246). It is also regarded as proven that PCP is capable of preventing the 25 destruction of nerve cells caused by cerebral ischaemia in rats (Sauer et al, Neurosci. Lett. 91, 1988, 327-332).
An investigation carried out to ascertain whether the compounds of formula (I) interact with the connecting point for PCP is described below. 3H-TCP, an analogue of 30 PCP, is used for this purpose. 9 A membrane preparation of rats • cortex is incubated with 3H-TCP, an analogue of phencyclidine (PCP) (Quirion & Pert 1982, Eur.J.Pharmaccol. 83:155). For test compound No.l: l-Amino-3,5-dimethyladamantane, the interaction with the 5 TCP connecting point is determined in the competition experiment. This shows that test compound No. 1 is highly effective in displacing TCP from the bond. The IC50-value is 89 nM. This shows that test compound No. 1 attaches itself to NMDA receptor channels at the point where the 10 NMDA antagonist attacks PCP.
B. Blocking of NMDA receptor channels The following test shows that the compounds according to the invention corresponding to formula (I) block the NMDA receptor channel in the same way as PCP.
In the patch clamp experiment, the current through NMDA activated membrane channels of cultured spinal marrow neurones (mouse) is measured (Hamill et al 1981, Pflugers Arch. 312: 85-100). The current signal of the cell is integrated over a period of 2 0 seconds after administra-20 tion of 20 /iM NMDA and evaluated as control ^response (Ac) . When 20 nM NMDA and 6 jiM of an adamantane derivative are subsequently applied together, the strength of the substance activity can be determined as relative change of the control response, A/Ac (A = test response).
The results are shown in Table 1 below: Table 1 Compound No. 1-A/AC n 1 0.66±0.05 14 2 0. 44±0.08 7 3 0.58±0.07 7 4 0.5010.11 0.56±0.07 7 6 0.38±0.05 7 7 0.25±0.04 11 8 0.50±0.03 6 PCP 0.50±0.04 7 MK-801 0.60±0.05 22 Values are given as mean value ± S.E.M.
It will be seen from these results that the amino-adamantane derivatives of formula (I) are capable of blocking the NMDA receptor channel in the same way as has been described for PCP (Bertolini et al, Neurosci.
Lett. 84./ 1988, 351-355) and for 5-methyl-10,11-dihydro- % 5H-dibenzo[a,d]-cycloheptene-5,10-imine (Ml£-801) (EP-A 0 264 183).
C. Anticonvulsive action 4, 12, 36, 108 and 324 mg/kg of the test substance are applied intraperitoheally to mice (5 animals per dose). The supermaximal electric shock test was applied 4 0 minutes after administration of the substance in order to ascertain the protection provided by the substance against cramps. The protected animals were added up over all doses (Score; Maximum = 25 animals). 11 The results are shown in Table 2 below.
Table 2 Compound Anticonvulsive Mean value ED50 No. action (Score) (mg/kg) 1 18 16 16 16.3 16 2 15 14 12 13.7 30 4 16 16 11 14.3 24 5 17 17 17.0 13 Standards: PCP 19 19.0 9 MK-801 25 25.0 <1 2 0 The ED5Q-values were estimated by the method of Litchfield and Wilcoxon (1949).
% \ The results show that amino-adamantane derivatives of formula (I) are capable of protecting against electrically induced cramps. They are therefore anti-convulsive.
D. Correlation between channel blockage and anticonvulsive action A test is carried out to ascertain whether the action of the tested adamantane derivatives 1-8 on the NMDA receptor channel (in vitro) is associated with the anti-convulsive 30 action (in vivo). An x-y diagram of the two test parameters is drawn up for this purpose, as shown in Figure 1. 12 It may be seen from this that a correlation between blockage of the NMDA receptor channel and the anticonvulsive action exists for the adamantanes of formula (I) * E. Protection against cerebral ischaemia The two carotid arteries of rats are closed for 10 minutes and the blood pressure lowered during this period to 60 - 80 mg Hg by the removal of blood (Smith et al 1984, Acta Neurol. Scand. 69: 385, 401). The ischaemia is 10 then terminated by opening the carotids and reinfusing the blood which had been removed. Seven days thereafter the brains of the experimental animals are investigated histologically for cell changes in the CA1-CA4 region of the hippocampus and the percentage proportion of neurone 15 destructions is determined. The effect of Test compound No.l is tested after a single intraperitoneal administration of 5 mg/kg and 20 mg/kg, respectively, one hour before the ischaemia.
The results are summarised in Table 3 below: % •s Table 3 Area Control Test Compound No. 1 mg/kg fn=5) 20 mg/kg fn=6) CA1 80.2±1.5 83.0+2.2 53.1+6.1** CA3 3.6±1.1 7.3±1.8 2.711.0 CA4 1.4±0.4 3.711.7 0.610.3 The values are given as a percentage of the damaged neurones + S.E.M.
Significance of the mean value difference: **p < 0.01 (U 13 test) The results show that preischaemic application of 20 mg/kg of Test compound No.l produces a statistically significant reduction in the post-ischaemic neuronal cell 5 damage in the cal area of rats' hippocampus. Physiological parameters (e.g. blood pressure, body temperature) are not altered during the treatment. The results also show that the compounds corresponding to formula (I) have a neuroprotective action in cerebral ischaemia.
The invention will now be illustrated with the aid of examples.
Example 1 Injection solution 0.5% of active substance and 0.8% of sodium chloride DAB 9 15 are dissolved in twice distilled water to prepare a 0.5% solution. The solution is filtered through a filter with antimicrobial layer, introduced into 2 ml ampoules and heat sterilised in the autoclave at 120*C for 20 minutes.
Example 2 % Solution 1% Active substance is dissolved in demineralised water. The solution is filtered before it is filled into ampoules.
Example 3 Tablets 1 Tablet consists of: 14 Active substance 10.0 mg Lactose 67.5 mg Microcrystalline cellulose 18.0 mg Talc 4.5 ma 100.0 mg The substances are mixed together and compressed into 100 mg tablets by the direct tabletting process without granulation.
Example 4 Coated tablets 6 mm tablet centres weighing 100 mg are prepared as described under "Tablets". The coating is applied by the sugar coating process: The centre is first covered with coating suspension, then coloured with colouring syrup and 15 finally polished.
The tablet coating consists of: Sugar 65. 0 * mg Talc 39.0 mg Calcium carbonate 13.0 mg Gum arabic 6.5 mg Corn starch 3.7 mg Shellac 1.1 mg Polyethylene glycol 6000 0.2 mg Magnesia usta 1.3 mg Dyestuff 0.2 mq 130. 0 mg Total weight of coated tablet = 230 mg Example 5 A 0.01% infusion solution is prepared by dissolving 0.01% of active substance and 5% of laevulose in twice distilled water. The solution is filtered through an antimicrobial 5 filter, introduced into 500 ml infusion bottles and sterilised.
The example relates to 50 mg of active substance per individual dose.
Example 6 Synthesis of l-Amino-3-isopropvl-adamantane hydrochloride (Test compound No. 3) A. Preparation of Adamantane carboxylic acid methyl ester(I) 1.0 mol of Adamantane carboxylic acid is stirred up in 600 15 ml of methanol. 1.53 mol of acetyl chloride are added dropwise within 1 hour under ice cooling. The ice bath is removed and the reaction mixture is left to warm up to room temperature and then heated under reflux for 3 hours. The reaction mixture is concentrated by evaporation under 20 vacuum and distilled (97% yield).
B. Preparation of 2-Adamantyl-propan-2-ol(II) 0.5 mol of magnesium filings are introduced into 50 ml of absolute ether and 0.5 mol of methyl iodide are added dropwise at such a rate with exclusion of moisture that 25 the ether boils. The reaction mixture is then heated on a water bath until all the magnesium has dissolved. 16 A solution of 0.2 mol of adamantane carboxylic acid methyl ester(I) in absolute ether is added dropwise to this solution at room temperature. When all the adamantane carboxylic methyl ester has been added, the reaction 5 mixture is heated to reflux for 3 hours. The product is hydrolysed with ice after cooling and ammonium chloride solution is added until the precipitate has dissolved. The ether phase is separated off, the aqueous phase is washed twice with ether and the combined organic phases are 10 washed with sodium bicarbonate solution, dried and concentrated by evaporation under vacuum. (Yield 93%) C. Preparation of Isopropenyl-adamantane(III) 0.25 mol of 2-Adamantyl-propan-2-ol(II) are stirred in 500 ml of acetic acid anhydride at 160*C for 12 hours. The 15 reaction mixture is then poured out on to 1 litre of ice water and extracted with ether. The combined organic phases are dehydrated with magnesium sulphate, filtered and concentrated by evaporation under vacuum. The residue is distilled under vacuum. (Yield 66%) D. Preparation of Isopropyl-adamantane(IV) 0.074 mol of Isopropenyl-adamantane(III) are dissolved in 100 ml of absolute ethan'ol. 4 g of palladium (5% on active charcoal) are added and the mixture is hydrogenated at room temperature for 24 hours with stirring. The catalyst 25 is then removed by filtration and the solvent is removed under vacuum. (Yield 91%) E. Preparation of l-Bromo-3-isopropyl-adamantane(V) A ten-fold excess of bromine (0.33 mol) is added to 0.034 17 mol of isopropy 1-adamantane (IV) . The mixture is slowly heated and stirred under reflux for 4 hours. It is then left to cool and poured out on ice water. Sodium sulphite is added to decompose the excess bromine until the aqueous 5 solution is decolourized. The reaction mixture is then extracted with ether and the combined organic phases are washed with sodium bicarbonate solution, dehydrated with magnesium sulphate, filtered and concentrated by evaporation under vacuum. The residue obtained is recrystallised 10 from methanol. (Yield 83%) F. Preparation of l-Formyl-amido-3-isopropyl-adamantane(VI) 0.028 mol of l-Bromo-3-isopropyl-adamantane(V) are heated under reflux with 4 0 ml of formamide for 12 hours. After 15 cooling, the reaction mixture is poured out on water and extracted with dichloromethane. The combined organic phases are dehydrated with magnesium sulphate, filtered and concentrated by evaporation under vacuum. (Yield 82%) G. Preparation of l-Amino-3-isopropyl-adamantane hydro-20 chloride 100 ml of 15% hydrochloric acid are added to 0.023 mol of l-formyl-amido-3-isopropyl-adamantane(VI) and the mixture is heated to boiling for 24 hours. After cooling, the precipitate is filtered off and recrystallised from 25 isopropanol. (Yield 57%) 18 Example 7 Synthesis of l-Amino-3-cvclohexvl-adamantane hydrochloride (Test compound No. 7) A. Preparation of 1-phenyl-adamantane (I) 0.068 mol of Iron(III) chloride are heated to boiling in 20 ml of absolute benzene. 0.0186 mol of 1-bromo-adaman-tane dissolved in 30 ml of absolute benzene are added dropwise with stirring. The reaction mixture is then heated to boiling for 3 hours. After cooling, the mixture 10 is poured out on ice/hydrochloric acid, the organic phase is separated off and the aqueous phase is extracted twice with benzene. The combined organic phases are washed with water, dehydrated with calcium chloride, filtered and concentrated by evaporation under vacuum. The residue is 15 recrystallised from methanol. (Yield 80%) B. Preparation of l-Hydroxy-3-phenyl-adamantane(II) •\ 0.0095 mol of 1-phenyl-adamantane are added to a solution of 0.03 mol of chromium trio'xide in 20 ml of glacial acetic acid and 20 ml of acetic acid anhydride at 0*C and 20 the reaction mixture is- stirred at 4*C for 24 hours. The mixture is then poured out on water and extracted three times with pentane. The organic phase is washed with saturated sodium chloride solution, dehydrated over magnesium sulphate, filtered and concentrated by evapora-25 tion under vacuum. The residue is hydrolysed with 20 ml of 2N NaOH and 50 ml of methanol. The methanol is subsequently removed under vacuum and the residue is diluted with water. It is then extracted three times with ether. The 19 organic phase is dried, filtered and concentrated by evaporation under vacuum. The residue is recrystallised from cyclohexane. (Yield 50%) Lit.: H.Stetter, M.Schwarz and A.Hirschhorn, Chem.Ber. 5 (1959) 92, 1629-35.
C. Preparation of l-Bromo-3-phenyl-adamantane(III) 0.03 mol of 3-phenyladamantanol (II) and 100 ml of 40% HBr are stirred together in glacial acetic acid for 20 minutes at 60 *C and for 3 0 minutes at room temperature. The 10 reaction mixture is then diluted with water and extracted with ether. The combined organic extracts are washed with sodium chloride solution, dehydrated with magnesium sulphate, filtered and concentrated by evaporation under vacuum. The residue is recrystallised from methanol. 15 (Yield 68%) Lit.: W.Fischer and C.A.Grog, Helvetica Chim.Acta (1976), 59,1953.
D. Preparation of l-Formyl-amido-3-phenyl-adamantane(IV) * 0.03 mol of l-bromo-3-phenyl-adamantane(III) are heated 20 under reflux together with 50 ml of formamide for 12 hours. After cooling, the reaction mixture is poured out on water and extracted with dichloromethane. The combined organic phases are dehydrated with magnesium sulphate, filtered and concentrated by evaporation. (Yield 80%) E. Preparation of l-Amino-3-phenyl-adamantane hydrochloride (V) 0.02 mol of l-formyl-amido-3-phenyl-adamantane(IV) are heated to boiling with 100 ml of 15% hydrochloric acid for 24 hours. After cooling, the precipitate is filtered off and recrystallised from isopropanol. (Yield 60%) F. Preparation of l-Amino-3-cyclohexyl-adamantane(VI) 0.011 mol of l-Amino-3-pheny 1-adamantane(V) are dissolved in 150 ml of glacial acetic acid, 0.3 g of platinum oxide 5 (1% on active charcoal) are added and the substance is hydrogenated in a Parr apparatus at 35*C under a hydrogen pressure of 3 bar. The catalyst is then filtered off and the filtrate is concentrated by evaporation. The residue is taken up with methanol and the product is precipitated 10 with ether, suction filtered and dried. (Yield 70%) Example 8 Synthesis of l-Amino-3.5-dimethvl-7-ethvl-adamantane hydrochloride (Test compound No.8) A. Preparation of l-Bromo-3,5-dimethyl-adamantane(I) A ten-times excess of bromine (5 mol) is added to 0.5 mol of 1,3-dimethyl-adamantane. The mixture is slowly stirred under reflux for 4 hours. It is then left t*o cool and poured out on ice water. The excess bromine is decomposed with sodium sulphite until the aqueous solution is 20 decolourized. The solution is then extracted with ether and the combined organic phases are washed with sodium bicarbonate solution, dehydrated with magnesium sulphate, filtered and concentrated by evaporation under vacuum. The residue obtained is recrystallised from methanol. (Yield 25 83%) B. Preparation of 1-(2-Bromo-ethyl)-3,5-dimethyl-adamantane (II ) 21 0.6 mol of aluminium bromide are added to 1.4 mol of l-bromo-3,5-dimethyl-adamantane(I) in hexane at -75*C. Ethylene is then passed through the solution for 20 to 30 minutes and the reaction mixture is stirred for 5 minutes 5 and poured out on to ice water. It is extracted with ether and the organic phase is dehydrated and concentrated by evaporation. The residue is recrystallised from methanol. (Yield 48%) C. Preparation of 1,3-Dimethyl-5-ethyl-adamantane(III) 0.5 mol of l-(2-bromo-ethyl)-3,5-dimethyl-adamantane(II) are dissolved in toluene and 0.55 mol of sodium-bis(2-methoxy-ethoxy)-dihydro-aluminate are added and the mixture is heated to boiling for 3 hours. After hydrolysis, the organic phase is separated off, dehydrated with 15 magnesium sulphate and concentrated by evaporation under vacuum. The residue is purified by vacuum distillation. (Yield 86%) D. Preparation of l-Bromo-3,5-dimethyl-7-ethyl-adamantane(IV) * N A ten-fold excess of bromine (4 mol) is added to 0.4 mol of 1, 3-dimethyl-5-ethyl-adamantane(III) . The reaction mixture is slowly heated and stirred under reflux for 4 hours. It is then left to cool and poured out on ice water. The excess bromine is decomposed with sodium 25 sulphite until the agueous solution is decolourized. The solution is then extracted with ether and the combined organic phases are washed with sodium bicarbonate solution, dehydrated with magnesium sulphate, filtered and concentrated by evaporation under vacuum. The residue 30 obtained is recrystallised from methanol. (Yield 86%) 22 E. Preparation of l-Formyl-amido-3,5-dimethyl-7-ethyl-adamantane(V) 0.2 mol of l-bromo-3,5-dimethyl-7-ethyl-adamantane(IV) are heated under reflux with 150 ml of formamide for 12 hours. 5 After cooling, the reaction mixture is poured out on water and extracted with dichloromethane. The combined organic phases are dehydrated with magnesium sulphate, filtered and concentrated by evaporation under vacuum. (Yield 82%) F. Preparation of l-Amino-3,5-dimethyl-7-ethyl-adamantane 10 hydrochloride(VI) 100 ml of 15% hydrochloric acid are added to 0.2 mol of l-formyl-amido-3,5-dimethyl-7-ethyl-adamantane(V) and the mixture is heated to boiling for 24 hours. After cooling, the precipitate is filtered off and recrystallised from 15 isopropanol. (Yield 57%) Example 9 * \ Synthesis of l-N-MethvIamino-3.5-dimethvl-adamantane (Test compound No. 5) 0.1 mol of the correspondingly substituted amino-adamant-20 ane (l-amino-3,5-dimethyl-adamantane) are dissolved with 0.15 mol of chloroformic acid ethyl ester and potassium carbonate in acetone and heated to reflux for 8 hours. After cooling, the reaction mixture is filtered, the solvent is drawn off and the residue is dehydrated. 25 0.1 mol of sodium-bis-(2-methoxy-ethoxy)-dihydroaluminate in toluene is added to the crude product (0.05 mol) and 23 the mixture is heated to boiling for 3 hours. After cooling, it is hydrolysed with dilute HCl and the organic phase is dehydrated and concentrated by evaporation.
The crude product is purified by distillation.
Example 10 Synthesis of l-Amino-3-ethvl-5-phenvl-adamantane A. Preparation of l-bromo-3-ethyl-adamantane(I) A ten-fold excess of bromine (0.33 mol) is added to 0.034 mol of ethyl-adamantane. The mixture is slowly heated and 10 stirred under reflux for 4 hours. It is then left to cool and poured out on ice water. The excess bromine is decomposed with sodium sulphite until the aqueous solution is decolourized. The solution is then extracted with ether and the combined organic phases are washed with 15 sodium bicarbonate solution, dehydrated with magnesium sulphate, filtered and concentrated by evaporation under vacuum.
The residue obtained is recrystallised from methanol.
(Yield 83%) B. Preparation of l-Ethyl-3-phenyl-adamantane(II) 0.068 mol o.f iron(III) chloride are heated to boiling in 20 ml of absolute benzene. 0.0186 mol of l-bromo-3-ethyl-adamantane(I) dissolved in 30 ml of absolute benzene are added dropwise with stirring. The reaction mixture is then 25 heated to boiling for 3 hours. The mixture is poured out f on ice-hydrochloric acid after cooling, the organic phase is separated off and the aqueous phase is extracted twice >- with benzene. The combined organic phases are washed with water, dehydrated with calcium chloride, filtered and 24 concentrated by evaporation under vacuum. The residue is recrystallised from methanol. (Yield 80%) C. Preparation of l-Ethyl-3-hydroxy-5-phenyl-adamantane(III) 0.0095 mol of l-ethyl-3-phenyl-adamantane(II) are added to a solution of 0.3 mol of chromium trioxide in 20 ml of glacial acetic acid and 20 ml of acetic acid anhydride at 0*C and the mixture is stirred at 4*C for 24 hours. It is then poured out on water and extracted three times with 10 pentane. The organic phase is washed with saturated sodium chloride solution, dehydrated over magnesium sulphate, filtered and concentrated by evaporation under vacuum. The residue is hydrolysed with 20 ml of 2N NaOH and 50 ml of methanol. The methanol is then removed under vacuum and 15 the residue is diluted with water. It is then extracted three times with ether. The organic phase is dehydrated, filtered and concentrated by evaporation under vacuum. The residue is recrystallised from cyclohexane.
(Yield 50%) Lit.: H.Stetter, M.Schwarz and A.Hirschhorn, * Chem. Ber. (1959), 92, 1629-35 D. Preparation of l-Bromo-3-ethyl-5-phenyl-adamantane(IV) 0.03 mol of l-ethyl-3-hydroxy-5-phenyl-adamantane(III) and 100 ml of 40% HBr are stirred together in glacial acetic 25 acid for 20 minutes at 60 *C and 30 minutes at room temperature. The reaction mixture is then diluted with water and extracted with ether. The combined organic extracts are washed with sodium chloride solution, dehydrated with magnesium sulphate, filtered and con-3 0 centrated by evaporation under vacuum. The residue is recrystallised from methanol. (Yield 68%) Lit.: W.Fischer and C.A.Grog, Helvetica Chim.Acta (1976), 59, 1953 E. Preparation of l-N-Formyl-3-ethyl-5-phenyl-5 adamantane(V) 0.03 mol of l-ethyl-3-hydroxy-5-phenyl-adamantane(IV) and 50 ml of formamide are together heated under reflux for 12 hours. After cooling, the reaction mixture is poured out on water and extracted with dichloromethane. The combined 10 organic phases are dehydrated with magnesium sulphate, filtered and concentrated by evaporation. (Yield 80%) F. Preparation of l-amino-3-ethyl-5-phenyl-adamantane hydrochloride (VI) 0.02 mol of l-N-Formyl-3-ethyl-5-phenyl-adamantane(V) and 15 100 ml of 15% hydrochloric acid are heated to boiling for 24 hours. After cooling, the precipitate is filtered off and recrystallised from isopropanol. (Yield 60%) 26

Claims (1)

1.ent Claims The use of adamantane derivatives corresponding to the following general formula wherein R^ and R2 are identical or different and stand for hydrogen or straight chain or branched alkyl groups having 1 to 6 carbon atoms or together with N represent a heterocyclic group having 5 or 6 ring members, R3 and R4 are identical or different and are selected from hydrogen, a straight chain or branched alkyl group having 1 to 6 carbon, atoms, a * cycloalkyl group having 5 or 6 carbonNatoms or the phenyl group and R5 denotes hydrogen or a straight chain or branched C^-Cg-alkyl' group- and their pharmaceutically acceptable salts for the preparation of a medicament for the treatment of damage to brain cells due to cerebral ischaemia. Use according to Claim 1 wherein Rj_, R2 and R5 denote hydrogen. R (I) 27 Use according to Claim 2 wherein Rlf R2 and R:5 denote hydrogen and R3 and R4 denote methyl. Use according to Claim 2 wherein R1# R2 and R5 denote hydrogen and R3 and R4 denote ethyl. Use according to Claim 1 wherein R^, R2, R4 and R5 denote hydrogen and R3 denotes ethyl, isopropyl or cyclohexyl. Use according to Claim 1 wherein R2 and R5 denote hydrogen. Use according to Claim 6 wherein R3 and R4 denote methyl, R2 and R5 denote hydrogen and R^ denotes methyl or ethyl. Use according to Claim 1 wherein R^ and R2 denote hydrogen. Use according to Claim 8 wherein R^ and R2 denote hydrogen, R3 denotes ethyl and R5 and R4 denote methyl. Use according to Claim 1, wherein the adamantane derivative is l-amino-3-ethyl-5,7-dimethyl-adamantane. Use of adamantane derivatives as disclosed in claims 1 to 9 for the preparation of a medicament for the treatment of Alzheimer's disease. l-Amino-3-cyclohexyl-adamantane. 28 13. Use according to Claim 1, substantially as hereinbefore described. F. R. KELLY & CO., AGENTS FOR THE APPLICANTS. % 4 29
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